(1) Field of the Invention
This invention relates to a microencapsulation method for the preparation of a controlled oral drug delivery system. In particular, it relates to a method for microencapsulation of oil droplets containing a drug for oral administration.
In particular, it relates to a method for microencapsulation of a drug for oral administration using biodegradable and biocompatible materials such as polysaccharide that have a metal chelating capacity for the purpose of minimizing gastric upset or damage to the stomach.
More particularly, it relates to a method for microencapsulation of oil-containing drugs for oral administration using a biodegradable and biocompatible material such as polysaccharide for the purposes of minimizing the degradation of the drug caused by hepatic first-pass metabolism by inducing lymphatic absorption of the drug, and the degradation of the drug in the strong acidic condition of gastric juice.
Recently, research groups have focused their studies on a desirable drug carrier system because the existing methods for medicating drugs by oral administration or injection suffer from many problems with regard to
1) the degradation of the drug by hepatic first-pass metabolism, PA1 2) the severe gastric upset or damage to the stomach by the drug's activity, PA1 3) the degradation of the drug in the stomach by the strong acidic condition of gastric juice.
However, the existing methods for drug administration using oral route or injection continue to be used because of their convenience.
Although in principle the entire gastrointestinal tract is capable of drug absorption, the small intestine is the major site of absorption for the drug. A drug molecule, after diffusing through the mucosa of the intestine, is accessible to both lymphatic and blood circulation. If a drug is administered via the oral route, it must pass through the gut wall and then through the liver before reaching the systemic circulation and its site of action. Extensive hepatic first-pass metabolism in the liver is often encountered, and a fraction of the dose administered may be eliminated before reaching the systemic circulation.
Accordingly, an increased amount of drug dose and dosing frequency are required to maintain blood levels within the therapeutic range. This results in severe gastric upset or damage to the stomach.
Furthermore, for a cancer patient, the anticancer drugs given orally cause adverse effects because most antitumor agents are not selective, but are highly toxic for both cancer and normal cells.
In lymphatic absorption, drug molecules enter directly into systemic circulation by bypassing the liver. Thus, the overall blood levels of drugs which undergo significant metabolism in the liver can be significantly increased if they can be directed to the lymphatic fluid.
In general, the lymphatic system is not an important route for drug entry into the body except for highly lipophilic compounds, such as dietary fat, cholesterol, and lipid soluble vitamins.
In the present invention, in order to use the advantages of the lymphatic system as a drug absorption route, the inventors attempted to use an emulsion as drug carrier systems to transport medical drugs. The oil emulsions are absorbed easily into lymphatic capillaries and transported to regional lymph nodes. As a result, the oil emulsion can be considered as a drug carrier to the lymphatic system by oral administration as well as by injection into tissues.
Accordingly, an emulsion containing anticancer agent is available in chemotherapeutic drug dosage form for lymph node metastasis, which is most common in human cancer.
In the case of oral administration of an emulsion containing an anticancer drug, most anticancer drugs are released in the stomach. Therefore, anticancer agents can not react in the small intestine. Thus, in the case of oral administration, the chemotherapeutic effect of anticancer drugs is limited only to stomach cancer. (CRC: Critical Review in Therapeutic Drug Carrier Systems, vol. 2 No. 3, pp. 245, 1986)
(2) Description of the Prior Art
As to the conventional method for microencapsulating liquid fatty material such as by oil emulsion, U.S. Pat. Nos. 3,008,083; 3,749,799; and 3,819,838 disclose a solidification method of the capsule material, gelatin, by rapidly lowering the temperature and subsequent dehydration. While methods such as those disclosed in the patent literature set forth above have achieved some significant commercial success, difficulties have sometimes been encountered in rapidly inducing solidification of the microencapsulating material.
British Pat. No. 2,086,835 provides a process for encapsulating oils using polysaccharide as a material for bead matrix. However, this method produces shape-retaining, substantially water insoluble micro-beads containing thousands of oil droplets in the bead matrix. This process can not provide a microencapsulated emulsion which is individually microencapsulated oil droplets in the powdery state having a diameter of less than 5 .mu.m.
Japan Patent No. 59-228930 provides a process for encapsulating olive oil using sodium alginate as capsule material. In this method, the core and capsule materials flow down as double layers on a vertical cone vibrated supersonically and the microcapsules are received in hardening solution or dried to harden the capsule material. This method requires a very complex apparatus for microencapsulation.